Project 2: Impact of immune-based intervention on viral rebound in orally SHIV infected infant monkeys

摘要-项目2(负责人：杜克大学吉纳维芙·福达博士) 全世界有180多万儿童感染艾滋病毒，每年有150,000多名儿童感染艾滋病毒 感染就会发生。目前的护理标准要求感染艾滋病毒的儿童终身接受每日抗逆转录病毒治疗 治疗(ART)。然而，抗逆转录病毒疗法并不能治愈艾滋病毒，这是因为重建的病毒库持续存在。 治疗中断后的感染。减少病毒库大小的治疗干预措施 当抗逆转录病毒治疗中断时，可能会推迟病毒反弹。这样的水库减少可以很早地实现 ART启蒙，但对于大约一半来自出生后的儿童艾滋病毒病例来说，这是不现实的 感染通过母乳传播艾滋病毒，因为他们的诊断被推迟了。因此，出生后感染 儿童将从辅助疗法的发展中受益匪浅，包括基于免疫的策略。 事实上，研究表明，抗体被动免疫和治疗性疫苗接种可以影响 病毒储存库，但它们在成熟的婴儿免疫系统中的相关性和作用尚不清楚。一个 开发针对出生后感染婴儿的免疫治疗干预措施的第一步将是 要求确定与母乳传播后的病毒控制相关的免疫机制。因此， 本项目的目标是确定母乳中病毒反弹的免疫相关因素 变速箱。我们的中心假设是ART中特异性抗病毒免疫反应的增强- 经治疗的猴-人类免疫缺陷病毒(SIV)感染的婴儿恒河猴(RMS)，通过 抗体被动免疫或通过接种，会减少病毒库，延缓病毒反弹 治疗中断后。我们提出了以下目标：1)评估病毒特异性免疫的动力学 ART治疗SHIV感染的婴儿RMS的反应；2)确定多克隆辅助治疗的影响 多功能抗病毒抗体对婴儿RM母乳传播和ART模型中病毒反弹的影响； 3)评价疫苗接种增强T细胞应答对SHIV病毒反弹的影响。 接受抗逆转录病毒治疗的婴儿RMS感染。该项目将与建议计划的其他项目进行交互，并利用 行政和统计核心、非人类灵长类核心和病毒学核心的服务。这 该项目将确定与水库清除和/或病毒反弹延迟相关的免疫相关因素 与出生后传播高度相关的动物模型，从而指导儿科特异性免疫系统的设计 以艾滋病毒功能性治疗为基础的干预措施。

ABSTRACT – Project 2 (Leader: Dr. Genevieve Fouda, Duke University) More than 1.8 million children world-wide live with HIV, and every year more than 150,000 new pediatric HIV infections occur. Current standard of care commits HIV-infected children to lifelong, daily antiretroviral treatment (ART). However, ART does not cure HIV due to the persistence of virus reservoirs that re-establish infection following treatment interruption. Therapeutic interventions that lower the size of the virus reservoir could delay virus rebound when ART is interrupted. Such reservoir reduction can be achieved by very early ART initiation, but this is not practical for the roughly half of pediatric HIV cases stemming from postnatal infection via breast milk HIV transmission because their diagnosis is delayed. Thus, postnatally infected children would benefit greatly from development of adjunct therapies, including immune-based strategies. Indeed, studies have indicated that antibody passive immunization and therapeutic vaccination can impact virus reservoirs, but their relevance and effect in the maturating infant immune system remains unknown. A first step toward development of immunotherapeutic interventions for postnatally infected infants thus will require identifying the immune mechanisms associated with virus control after breast milk transmission. Thus the objective of this Project is to identify immune correlates of virus rebound in the setting of breast milk transmission. Our central hypothesis is that enhancement of specific antiviral immune responses in ART- treated, simian-human immunodeficiency virus (SHIV)-infected infant rhesus macaques (RMs), either through antibody passive immunization or through vaccination, will reduce the virus reservoir and delay virus rebound after treatment interruption. We propose the following aims: 1) Assess kinetics of virus-specific immune responses in ART treated SHIV-infected infant RMs; 2) Define the impact of adjunct therapy with polyclonal polyfunctional antiviral antibodies on virus rebound in an infant RM model of breast milk transmission and ART; and 3) Evaluate the impact of enhancing T cell responses through vaccination on virus rebound in SHIV- infected ART-treated infant RMs. This Project will interact with the proposed Program's other Project and utilize the services of the Administrative and Statistical Core, the Nonhuman Primate Core, and Virology Core. This Project will identify immune correlates associated with reservoir clearance and/or delay in virus rebound in a highly relevant animal model of postnatal transmission and thereby guide design of pediatric-specific immune- based interventions towards an HIV functional cure.